Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins

Wootton, Daniel G.; Diggle, Peter J.; Court, Joanne; Eneje, Odiri; Keogan, Lynne; Macfarlane, Laura; Wilks, Sarah; Woodhead, Mark; Gordon, Stephen B.

doi:10.1136/thoraxjnl-2016-208505

Cited by 16 publications

(13 citation statements)

References 10 publications

(12 reference statements)

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“…Our data suggest that the acute symptoms of pneumonia resolve completely in most patients; however, if pneumonia were to destabilise comorbidities, then the recovery pattern may resemble the “relapsing recurrences” paradigm. Recent work suggests that it may soon be possible to trial therapies aimed at enhancing the resolution of inflammation caused by pneumonia [ 33 ]. Measuring outcome in these trials will be challenging since most people survive an episode of CAP, and studies aimed at detecting changes in mortality would need to be very large since the effect size is likely to be small.…”

Section: Discussionmentioning

confidence: 99%

A longitudinal modelling study estimates acute symptoms of community acquired pneumonia recover to baseline by 10 days

et al. 2017

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Our aims were to address three fundamental questions relating to the symptoms of community-acquired pneumonia (CAP): Do patients completely recover from pneumonia symptoms? How long does this recovery take? Which factors influence symptomatic recovery?We prospectively recruited patients at two hospitals in Liverpool, UK, into a longitudinal, observational cohort study and modelled symptom recovery from CAP. We excluded patients with cancer, immunosuppression or advanced dementia, and those who were intubated or palliated from admission. We derived a statistical model to describe symptom patterns.We recruited 169 (52% male) adults. Multivariable analysis demonstrated that the time taken to recover to baseline was determined by the initial severity of symptoms. Severity of symptoms was associated with comorbidity and was inversely related to age. The pattern of symptom recovery was exponential and most patients’ symptoms returned to baseline by 10 days.These results will inform the advice given to patients regarding the resolution of their symptoms. The recovery model described here will facilitate the use of symptom recovery as an outcome measure in future clinical trials.

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Section: Discussionmentioning

confidence: 99%

A longitudinal modelling study estimates acute symptoms of community acquired pneumonia recover to baseline by 10 days

et al. 2017

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“…Therefore, time-dependent neutralisation of apoptotic cells, especially apoptotic neutrophils, and clearance of NETs have appeared to be important steps in the resolution phase and recovery from lung injury, since effective removal of dying cells (known as efferocytosis) plays a crucial role in the maintenance of tissue homeostasis [18]. Macrophage phagocytic function is typically associated with engulfment of dying cells; however, less is known about the mechanisms involved in NET clearance [19][20][21]. Besides the recently described benefit of DNase I in experimental sepsis, the role of macrophages in the clearance of NETs, including in conditions associated with development and resolution of ARDS, has not been determined [22].…”

Section: Introductionmentioning

confidence: 99%

Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS

et al. 2018

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Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.

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“…While this latter study in particular appears to discount a role for adjuvant therapy with statins in CAP, the issue of sub-groups of patients, such as those with pneumococcal CAP and those who smoke, 150 the influence of dose and type of statin, as well as the possible interactions of statins with macrolides, require further investigation. With respect to the latter two points, the findings of the "SNOOPI" Trial (simvastatin to modify neutrophil function in older patients with septic pneumonia") are of interest.…”

Section: Host-targeted Anti-inflammatory Activities Of Macrolidesmentioning

confidence: 97%

Pneumolysin as a potential therapeutic target in severe pneumococcal disease

Feldman

2017

Journal of Infection

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Acute pulmonary and cardiac injury remain significant causes of morbidity and mortality in those afflicted with severe pneumococcal disease, with the risk for early mortality often persisting several years beyond clinical recovery. Although remaining to be firmly established in the clinical setting, a considerable body of evidence, mostly derived from murine models of experimental infection, has implicated the pneumococcal, cholesterol-binding, pore-forming toxin, pneumolysin (Ply), in the pathogenesis of lung and myocardial dysfunction. Topics covered in this review include the burden of pneumococcal disease, risk factors, virulence determinants of the pneumococcus, complications of severe disease, antibiotic and adjuvant therapies, as well as the structure of Ply and the role of the toxin in disease pathogenesis. Given the increasing recognition of the clinical potential of Ply-neutralisation strategies, the remaining sections of the review are focused on updates of the types, benefits and limitations of currently available therapies which may attenuate, directly and/or indirectly, the injurious actions of Ply. These include recently described experimental therapies such as various phytochemicals and lipids, and a second group of more conventional agents the members of which remain the subject of ongoing clinical evaluation. This latter group, which is covered more extensively, encompasses macrolides, statins, corticosteroids, and platelet-targeted therapies, particularly aspirin.

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Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins

Cited by 16 publications

References 10 publications

A longitudinal modelling study estimates acute symptoms of community acquired pneumonia recover to baseline by 10 days

A longitudinal modelling study estimates acute symptoms of community acquired pneumonia recover to baseline by 10 days

Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS

Pneumolysin as a potential therapeutic target in severe pneumococcal disease

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